Recent evidence indicates that microglia, innate immune cells of the brain, become more reactive with age. A potential consequence of a significant reactive microglia population is an amplified neuroinflammatory response to immune activation. This premise is supported by our recent study demonstrating that peripheral stimulation of the innate immune system with lipopolysaccharide (LPS) caused an exaggerated neuroinflammatory cytokine response and prolonged sickness behavior in aged BALB/c mice. Importantly, excessive or chronic exposure to inflammatory cytokines may be permissive to cognitive and behavioral complications in the elderly. In this application, we show that an LPS-exacerbated inflammatory cytokine response in the aged brain causes protracted depressive-like behavior and is associated with impaired brain metabolism of the monoamine neurotransmitter serotonin (5-HT), a critical regulator of mood and behavior. Our findings also indicate that this impaired brain 5-HT metabolism is a result of the heightened activity of indoleamine 2, 3 dioxygenase (IDO), an enzyme that catabolizes tryptophan (TRP). TRP is the rate limiting amino acid in 5-HT synthesis, so elevated TRP catabolism could reduce 5-HT-mediated neurotransmission leading to depressive behavior. Thus, a heightened neuroinflammatory response may underlie the depressive- related complications that frequently occur in the elderly. The objective of this project is to test the hypothesis that activation of the peripheral innate immune system in the aged promotes a prolonged inflammatory response in the hippocampus that disrupts 5-HT metabolism causing pronounced and long-lasting depressive symptoms. To address this issue, we propose two specific aims using an aged BALB/c mouse model. In the first aim we will delineate if attenuation of microglial activity prevents LPS-induced neuroinflammation, impaired 5-HT metabolism, and depressive-like behavior in aged mice. In the second aim we will determine if abrogation of IDO activity reverses these same biochemical and behavioral deficits in aged mice following LPS challenge. The goal of this proposal is to understand the effects of aging on depressive disorders associated with illness to develop strategies for therapeutic intervention to improve the likelihood of successful aging.